PROJECT SUMMARY/ABSTRACT The frequency and duration of heat waves have increased significantly over the last 50 years. Heat waves kill more people in a typical year than floods, tornadoes, and earthquakes combined and lead to excess emergency room visits and hospitalizations. In addition, heat increases the frequency of days with unhealthy levels of ground-level ozone and other harmful air pollutants. Air pollution caused three million deaths in 2012 globally and is causally linked to thromboembolic events, heart failure, and mucosal bleeding. The health impacts of extreme heat and air pollution will only intensify as a result of the changing climate, urbanization, and aging of the population. Older adults with chronic diseases, disabilities, and low socioeconomic status are vulnerable to the health effects of extreme heat and air pollution, not only due to particular sensitivities and/or low adaptive capacity, but also because of the multiple medications they often take. Although older adults make up only 13% of the population, they account for more than one-third of medication use in the US. However, the current evidence assessing health outcomes in relation to heat and air pollution lacks consideration of this critically important and modifiable risk factor and its interactions with heat and air pollution. Medication use is likely to play a key role in confounding the health effects of heat and air pollution and/or further increasing morbidity and mortality in older adults through its synergy with heat and/or air pollution. An interdisciplinary team of experts in climatology, biostatistics, data science, and pharmacoepidemiology will work closely to design the studies and analyze linked climate and health care data. Our study addresses the following specific aims: (1) assess the synergistic effect of extreme heat among users and non-users of commonly used medications in high-risk older adults; (2) assess the synergistic effect of air pollution, i.e., particulate matter (PM) and ozone, among users and non-users of medications known to cause cardiovascular, thromboembolic, and bleeding events in high-risk older adults; and (3) assess the synergistic effects of extreme heat and air pollution among users and non-users of the aforementioned medications. The study population will include older adults in the US and Taiwan for the period 2007-2016 who are at high risk for heat- and air pollution-related morbidity and mortality and adverse drug events due to their multimorbidity. The proposed study will not only quantify true casualties of extreme heat and air pollution in older adults, but also the modifiable individual-level factors that put this population at higher risk. The results of this study will redefine the safety of commonly used medications under conditions of extreme heat and air pollution. By assessing the interactions between extreme heat, air pollution, and medication in vulnerable old adults, the proposed study will produce rigorous and actionable evidence that will have a direct and long-lasting impact on clinical decisions and regulatory policies while improving understanding of underlying biological mechanisms.